Pancreatic ductal adenocarcinomas (PDAC) accounts for >30,000 deaths a year in the United States. Age is a significant risk factor for the development of the disease followed by inflammatory conditions of the pancreas, smoking, and rare familial genetic syndromes. Molecular profiling has revealed signature genetic lesions including K-Ras mutations, loss of p16lnk4a, p19Arf and p53 tumor suppressor genes, telomere attrition, and rampant genomic instability. Observations in human tumors suggest a role for tissue aging, cell turnover, and attendant telomere dysfunction in PDAC pathogenesis. Presently we do not possess a clear understanding of the relationship between activating oncogenic K-RAS lesions, telomere attrition, and loss of tumor suppressor checkpoints. Genetically engineered mouse (GEM) model systems have supported redundant roles of the p19Arf and p53 tumor suppressors. These data in mice contrast human data which have pointed towards non-overlapping roles for p19arf and p53 in that >50% PDACs incur the loss of both genes. Previously studies in the telomerase knock-out mouse have revealed the differential function of p19arf vs. p53 in response to telomere shortening- namely that in the presence of telomere attrition and the DNA damage response the p53 checkpoint constrainins tumor progression independent of p19arf function. Together human PDAC molecular data, genetically engineered mouse PDACs, and the telomerase knockout have prompted us to hypothesize that telomere-induced genomic instability may modulate the genetic interaction between p19arf and p53 in pancreatic cancer, conferring differential roles in constraint of tumor progression. In order to clarify the functions of these two crucial tumor suppressor genes we will generate mouse PDAC models harboring loss of either p19Arf or P53 on a background of telomere dysfunction. We hypothesize that this more accurate model will demonstrate the separate roles of p19Arf vs. p53 in the genomic and biological evolution of PDAC. Genomic and targeted molecular analysis of these tumors will provide insight into the influence of telomere dysfunction, DNA-damage response, and senescence on PDAC progression. The generation of murine tumors with a genomic complexity analogous to the human disease will offer the opportunity to study a hallmark feature of the disease (i.e., genomic instability) and enable comparative genomic profiling which will enhance the discovery of novel PDAC cancer genes.